tbuckley/cabot-search huggingface dataset:
Abstract 3558: Role of FLI portion of EWS::FLI in transcription regulation via modulation of chromatin 3D landscape in Ewing sarcoma
Authors: Ariunaa Bayanjargal, Cenny Taslim, Jesse Crow, Julia Selich-Anderson, Stephen L. Lessnick
Journal: Cancer Research (2023)

Abstract Ewing sarcoma is an aggressive bone-associated tumor currently treated with dose-intense chemotherapy, radiation, and surgery and it affects adolescents and young adults. The hallmark of Ewing sarcoma is a translocated fusion transcription factor named EWS::FLI that drives the oncogenic process. We hypothesize that FLI portion of EWS::FLI containing a crucial alpha-helix plays a novel role in transcription regulation of thousands of genes by modulating chromatin looping. The hypothesis is based on recent evidences from our lab: an alpha-helix immediately downstream of DNA binding domain as an important player in regulating transcriptional activity and that EWS::FLI has a substantial role in shaping the chromatin landscape of Ewing sarcoma cells. The objective of this study is to elucidate the mechanism underlying transcriptional regulation by FLI. We utilized knockdown/rescue experiments in which EWS::FLI was depleted with shRNA and replaced with constructs containing the ETS DNA Binding Domain (DBD) alone or DBD+ (DBD and 4th alpha-helix). The binding pattern and transcriptional regulation were assessed with CUT&amp;Tag and RNA-Seq respectively. The extent of roles each of these construct play in organization, structure, and function of chromatin are being assessed using Micro-C technique, a variation of Hi-C with improved resolution, higher signal-to-noise ratio and more information on chromatin domain boundaries and chromatin looping. The DNA binding and genomic localization of EWS::FLI was unaltered by the deletion surrounding the DNA binding domain (which contains a 4th alpha-helix) in A673 and TTC466 cells. Despite this similarity in genomic localization and binding, the transcriptional output driven by EWS::FLI was significantly diminished by the deletion. With this current study, we hope to understand if the flanking region neighboring the DNA binding domain contributes to the chromatin architecture remodeling function of EWS::FLI and whether this function could be attributed to the transcriptional output differences in the DBD and DBD+ conditions. Citation Format: Ariunaa Bayanjargal, Cenny Taslim, Jesse Crow, Julia Selich-Anderson, Stephen L. Lessnick. Role of FLI portion of EWS::FLI in transcription regulation via modulation of chromatin 3D landscape in Ewing sarcoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3558.
Abstract 6609: Detection of rare mutations, copy number variation, and DNA methylation in the same template DNA molecules
Authors: Yuxuan Wang, Christopher Douville, Joshua Cohen, Chetan Bettegowda, Nick Papadopoulos, Ken Kinzler, Bert Vogelstein
Journal: Cancer Research (2023)

Abstract The analysis of cell-free DNA (cfDNA) from plasma offers great promise for the earlier detection of cancer. At present, changes in DNA sequence, methylation, or copy number are the most sensitive ways to detect the presence of cancer. To increase the sensitivity of such assays, it would be useful to be able evaluate the same template molecules for all these changes. Here we report an approach, called MethylSaferSeqS, that achieves this goal, and can be applied to any standard library preparation method suitable for massively parallel sequencing. The innovative step was to copy both strands of each DNA-barcoded molecule with a primer that allows the subsequent separation of the original strands (retaining their 5-methylcytosine residues) from the copied strands (in which the 5-methylcytosine residues are replaced with unmodified cytosine residues). The original and copied strands are queried for epigenetic and genetic alterations, respectively. We applied this approach to plasma from 265 individuals, including 198 with cancers of the pancreas, ovary, lung or colon, and found the expected patterns of mutations, copy number alterations, and methylation. Furthermore, we could determine which original template DNA molecules were methylated and/or mutated. MethylSaferSeqS should be useful for addressing a variety of questions relating genetics and epigenetics in the future. Citation Format: Yuxuan Wang, Christopher Douville, Joshua Cohen, Chetan Bettegowda, Nick Papadopoulos, Ken Kinzler, Bert Vogelstein. Detection of rare mutations, copy number variation, and DNA methylation in the same template DNA molecules. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6609.
Abstract 5635: Joint secondary transcriptomic analysis of triple negative breast cancer offers a window into new therapeutic possibilities and biomarkers
Authors: Naomi Rapier-Sharman, Jenna Birchall Poulsen, Mauri E. Dobbs, Brett E. Pickett
Journal: Cancer Research (2023)

Abstract Breast cancer is a harmful growth of mutated breast tissue that is diagnosed in 2.3 million women yearly, and kills 685,000 patients (15%) each year around the world. Left unchecked, breast cancer can grow proliferatively and metastasize to new tissue sites, monopolizing the body’s energy supply and ultimately causing organ failure and death. Due to increased use of treatments targeting the breast tumor-specific markers Estrogen Receptor (ER), Progesterone Receptor (PR), and Human Epidermal growth factor Receptor 2 (HER2), patient survival of breast cancer has increased in recent years. However, patients with triple-negative breast cancer (TNBC), tumors lacking all three commonly-targeted biomarkers, suffer greater illness, experience more frequent relapse, and enjoy a shorter lifespan compared to other breast cancer patients due to the paucity of tumor-selective treatments for TNBC. Further research on TNBC is needed to understand targetable mechanisms and develop treatments capable of targeting the key mechanisms. To investigate the transcriptomic profiles of TNBC tumors, we performed a joint secondary analysis of publicly available RNA-sequencing data for TNBC, consisting of 214 relevant samples across 11 distinct studies in the NCBI Gene Expression Omnibus (GEO). We found ~12,500 significant differentially expressed genes (FDR p-value ⇐ 0.05) and 67 significantly modulated pathways (FDR p-value ⇐ 0.05). Additionally, our novel findings include candidates for drug repurposing, high-integrity predictive biomarkers, and potential new TNBC molecular mechanisms. We found several TNBC drug targets that have not yet been fully leveraged along with drugs that could likely be successfully repurposed for use in TNBC based on previous target history and our transcriptomic results. This joint secondary analysis opens the door to future therapeutic options that could increase patient survival once validated in the wet lab. Citation Format: Naomi Rapier-Sharman, Jenna Birchall Poulsen, Mauri E. Dobbs, Brett E. Pickett. Joint secondary transcriptomic analysis of triple negative breast cancer offers a window into new therapeutic possibilities and biomarkers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5635.
Abstract 4156: Site specific tumor response to combination chemotherapy and immune checkpoint inhibitor in the syngeneic Pan02 pancreatic ductal adenocarcinoma model
Authors: Andrew Wong, Patrick Fadden, Cara Clouse, Patrick Wood, Marianna Brown-Augustine, Fei Zhao, Elliot Ser, Joseph Kolb, Chassidy Hall, Elizabeth Rainbolt
Journal: Cancer Research (2023)

Abstract Syngeneic tumor models provide a platform to assess novel immune-oncology therapeutics in fully immuno-competent mice. A subcutaneous flank tumor implant provides a convenient and accessible location to monitor the tumor growth and response to therapy. However, the tumor microenvironment, and therefore, the responsiveness to immuno-oncology therapies, is greatly impacted by the location in which the tumor develops (Ho 2021, Oliver 2018). Given the potential of different immuno-suppressive features driven by the specific tumor location, we wanted to compare the tumor infiltrating leukocyte populations in the subcutaneous flank and orthotopic pancreatic Pan02 syngeneic models, as well as the response to standard of care therapies. Pan02 cells were either implanted orthotopically in the pancreas or subcutaneously in the flank and allowed to establish before dosing with either vehicle, oxaliplatin, anti-CTLA-4 or the combination of therapies. Established tumors from untreated orthotopic and flank models were sampled for flow cytometry to assess infiltration by a broad range of immune cell populations. Response to therapy was clearly dependent on tumor location with flank tumors being resistant to both monotherapy and combination therapy, while the orthotopic tumors responded modestly to monotherapy but displayed synergy with the combination therapy. The results suggest that for a given syngeneic tumor cell line with identical mutational load and antigenicity, we can generate unique tumor microenvironments dependent on implant location leading to different outcomes when testing novel immune-oncology therapies. These types of models can help define the context in which novel immune-oncology therapeutics can be expected to drive an effective immune response. Citation Format: Andrew Wong, Patrick Fadden, Cara Clouse, Patrick Wood, Marianna Brown-Augustine, Fei Zhao, Elliot Ser, Joseph Kolb, Chassidy Hall, Elizabeth Rainbolt. Site specific tumor response to combination chemotherapy and immune checkpoint inhibitor in the syngeneic Pan02 pancreatic ductal adenocarcinoma model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4156.
Abstract 693: A novel multi-subset dendritic cell vaccine derived from hematopoietic progenitor cells
Authors: Chun Yu, Richard L. Barrett, Ananya Zutshi, Karolina Palucka
Journal: Cancer Research (2023)

Abstract Owing to their molecular features, tissue localization and antigen processing and presentation capacity, dendritic cells (DCs) induce and regulate T cell immunity including licensing T cells to kill target cells. However, tumors often suppress DC differentiation and function leaving cancer patients with DC populations that are quantitatively and qualitatively deficient. This limits both the native immune responses to tumors as well as response to cancer therapy including immunotherapy. Thus, provision of healthy and functionally intact DCs to replace and correct the in vivo function offers an interesting therapeutic opportunity. DCs are composed of multiple subsets which specialize in activation of different immune effectors. Thus, a combination of DC subsets could generate a broad and diverse immunity targeted at cancer. To date, several attempts have been made to generate functional human DCs ex vivo for injection to patients, but the DC subtypes most effective in generation of anti-tumor responses—cDC1 and cDC2s—have proven difficult to make ex vivo using clinically compliant protocols. Here we show that cDC1s and cDC2s can be generated at high yield from hematopoietic progenitor cells (HPCs) from three different HPCs sources (including adult bone marrow) using clinically compliant protocols. We characterize the phenotype and functionality of these cells showing that both cDC1s and cDC2s efficiently process antigens, stimulate, and expand T cells specific for those antigens, and that those T cell populations display targeted killing of tumor cells in vitro. The ability to produce these subtypes using clinically compliant protocols is a major step towards developing effective autologous DC therapy for cancer patients. Citation Format: Chun Yu, Richard L. Barrett, Ananya Zutshi, Karolina Palucka. A novel multi-subset dendritic cell vaccine derived from hematopoietic progenitor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 693.
Abstract 4306: Identifying genetic dependencies of replication stress using interpretable artificial intelligence
Authors: Xiaoyu Zhao, Akshat Singhal, Trey Ideker
Journal: Cancer Research (2023)

Abstract Rapid proliferation is a hallmark of tumor cells, associated with sensitivity to chemicals that cause DNA replication stress (RS). Due to sustained proliferative signaling and/or defective DNA repair, cancer cells undergo persistent RS making them strongly dependent on the replication stress response (RSR). A consequence of this dependency is that RS becomes an exploitable therapeutic vulnerability in cancer treatment. Classical RS drugs work predominantly by interfering with DNA replication in dividing cells. Recently, an increasing number of drugs have been designed to specifically target RSR proteins. However, molecular pathways responsible for drug response are incompletely understood. Here we build an interpretable deep-learning model aimed at understanding mechanisms of susceptibility and resistance to replicative stress. Instead of associating genetic alterations with drug responses directly, our approach is to project individual mutations on a map of protein complexes and larger molecular assemblies with prior evidence for involvement in cancer. This approach is prompted and supported by the concept that cancer is a network-based disease arising from the action of hallmark cancer pathways. Through systematic interpretation, the model identifies 37 complexes that integrate rare alterations in hundreds of genes for accurate response prediction. The complexes, which cover roles in transcription, DNA repair, cell-cycle checkpoint, and immunity, are further investigated by directed genetic perturbations, validating 24 for which RS effects are phenocopied by CRISPR guide RNAs. For complexes with poorly characterized functions, further insights are obtained via their profiles of in-silico activation across RS agents. This study creates a library of system-level genetic vulnerabilities governing replication stress, with implications for drug selection and combination. Citation Format: Xiaoyu Zhao, Akshat Singhal, Trey Ideker. Identifying genetic dependencies of replication stress using interpretable artificial intelligence. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4306.
Abstract 3216: Comparative characteristics of stage I non-small cell lung cancer (NSCLC) patients segregated by quality of surgery and survival in a population-based cohort
Authors: Huibo Shao, Yu-Sheng Lee, Carrie Fehnel, Olawale Akinbobola, Andrea Saulsberry, Kourtney Dortch, Anberitha T. Matthews, Nicholas R. Faris, Matthew Smeltzer, Meredith A. Ray, Raymond U. Osarogiagbon
Journal: Cancer Research (2023)

Abstract Introduction. Poor quality NSCLC resection impairs survival, but some patients survive irrespective. We explored characteristics of patients in 4 cohorts defined by surgery quality and survival. Methods. We analyzed stage I resections in a population-based cohort surviving &amp;gt;120 days post-op from 2009-2018. Using the International Association for the Study of Lung Cancer’s stringent definition of ‘complete resection’ and 3-year survival as ‘good’, we categorized patients into 4 dyads: 1) Good surgery/good survival; 2) Good surgery/poor survival; 3) Poor surgery/good survival (reference); 4) Poor surgery/poor survival. We used Chi-square and Kruskal-Wallis test for description, multivariable multinomial logistic regression to estimate Odds Ratio (OR) of surgery quality and survival. Results. Of 1,515 patients, 31%, 7%, 51%, and 12% were in Groups 1-4, respectively. In the ‘mis-match dyads’ (Groups 2 and 3), Group 2 was more likely to be elderly (70 vs. 66, p&amp;lt;0.01), on Medicaid (p=0.01), have ever smoked (96% vs. 85%, p&amp;lt;0.01), have squamous cell carcinoma. Older (OR=1.06), male (OR=1.78), Medicaid patients (OR=2.16) with smoking history (OR=3.25) had poorer survival despite good surgery rather than survival despite bad surgery. With poor surgery, male (OR=2.01) patients tumor 2-3 and &amp;gt;3 cm (OR=1.77 and 1.64) had poorer survival; commercially insured patients had 36% reduced risk of poor survival. Compared to open thoracotomy, patients with robotic-assisted surgery were &amp;gt;4-fold more likely to have good surgery rather than poor surgery but good survival. Conclusion. Differentiating characteristics associated with good/bad survival after good/bad quality lung cancer surgery provide opportunity to compare biomarker profiles between dyads. Citation Format: Huibo Shao, Yu-Sheng Lee, Carrie Fehnel, Olawale Akinbobola, Andrea Saulsberry, Kourtney Dortch, Anberitha T. Matthews, Nicholas R. Faris, Matthew Smeltzer, Meredith A. Ray, Raymond U. Osarogiagbon. Comparative characteristics of stage I non-small cell lung cancer (NSCLC) patients segregated by quality of surgery and survival in a population-based cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3216.
Abstract 4842: Stress-induced mitochondrial adaptations in the polyaneuploid cancer cell state
Authors: Melvin Li, Laurie G. Kostecka, Sarah R. Amend, Kenneth J. Pienta
Journal: Cancer Research (2023)

Abstract Metastatic cancer is responsible for 90% of cancer deaths and is incurable due to resistance to all systemic anticancer therapies. While the classic model of therapy resistance is described by the presence of pre-existing resistant clones from tumor cell heterogeneity, our lab proposes the polyaneuploid cancer cell (PACC) state as a survival mechanism that cancer cells access when exposed to environmental stress such as hypoxia and chemotherapy. Our preliminary data has shown that cells that enter the PACC state exhibit repeated whole genome doubling, an increase in cell size, and proliferative arrest. In addition, we observed that a subpopulation of PACCs can give rise to non-polyploid, proliferative progeny after release from chemotherapy, modeling cancer recurrence. We hypothesize that the PACC state drives therapeutic resistance and elimination of this adaptive state is key in tackling the incurability of cancer. Mitochondria are essential organelles that have multifaceted roles in the cellular stress response and drug resistance. They integrate metabolic pathways for ATP generation and macromolecule biosynthesis, regulate apoptotic cell death, and activate stress response mechanisms in presence of drug treatment. We found that cells in the PACC state increase mitochondrial biogenesis and live cell imaging with MitoTraker dyes indicate that they also have higher activity per mitochondria when compared to parental cells. Cells that accessed the PACC state also had higher levels of TCA cycle metabolites including citrate, isocitrate, alpha-ketoglutarate, succinate, fumarate, and malate, suggesting increased mitochondrial function. Future work includes analysis of mitochondrial morphology via live cell confocal microscopy and of mitochondrial function via metabolic flux analysis on glucose and glutamine metabolism of cells in the PACC state. Our eventual goal is to characterize how cells in the PACC state alter their mitochondrial structure and function to survive therapy. Identifying vulnerabilities of the PACC phenotype will enable new therapeutic approaches to overcome therapy resistance in cancer. Citation Format: Melvin Li, Laurie G. Kostecka, Sarah R. Amend, Kenneth J. Pienta. Stress-induced mitochondrial adaptations in the polyaneuploid cancer cell state. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4842.
Abstract 3139: Pan-cancer splicing analysis reveals shared drivers of malignant transformation and survival
Authors: Anukana Bhattacharjee, Audrey Crowther, Guangyuan Li, Meenakshi Venkatasubramanian, Dan Schnell, Stuart Hay, Preeti Singh, Krithika R. Subramanian, Kashish Chetal, Xiaoting Chen, Aishwarya Kulkarni, Matthew T. Weirauch, Nathan Salomonis
Journal: Cancer Research (2023)

Abstract Alternative splicing is one of the primary mechanisms used to achieve mRNA transcript and proteomic diversity in higher order eukaryotes. In cancer, altered mRNA splicing can lead to aberrant protein products that promote oncogenic transformation, metastasis and confer chemotherapy resistance, due to splicing factor mutation or mis-expression. We hypothesize that the role of splicing imbalance in cancer is grossly underestimated and is likely regulated by the same recurrent global disruptions observed across human cancers. To determine common and malignancy specific splicing subtypes across cancer we designed a novel integrated computational workflow that uses genome variant data from RNA-Seq in conjunction with fully unsupervised analyses (NMF and SVM) to identify novel patient splicing-defined subtypes (OncoSplice). Applied to 20 adult and pediatric cancers with large cohorts, we identified common-recurrent splicing subtypes associated with MYC-hyperactivation and TGF-beta signaling, lineage reprogramming, tumor infiltration and broad mutation impacts. Such recurrent and tumor specific subtypes were frequently associated with poor prognosis and novel dominantly regulated driving splicing events (e.g., transcription factors). Broad splicing subtypes were associated with circadian dysregulation, as determined from normal healthy tissues (GTEx) and in many cases were found to phenocopy well-described splicing mutation impacts or were associated with new RNA-binding proteins (RBPs) evidenced by orthogonal computational predictions. Splicing subtype associated RBPs were frequently undergo autoregulation, as further evidenced by CLIP-Seq and RBP knockdown. To enhance the RNA community’s ability to explore hundreds of known and novel splicing variation across cancers and healthy tissues, we provide an interactive online splicing explorer at oncosplice.org. Together, these data highlight previously unknown regulatory relationships and prognostic associations in cancer associated with broad and targeted splicing regulation. Citation Format: Anukana Bhattacharjee, Audrey Crowther, Guangyuan Li, Meenakshi Venkatasubramanian, Dan Schnell, Stuart Hay, Preeti Singh, Krithika R. Subramanian, Kashish Chetal, Xiaoting Chen, Aishwarya Kulkarni, Matthew T. Weirauch, Nathan Salomonis. Pan-cancer splicing analysis reveals shared drivers of malignant transformation and survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3139.